Protein O-GlcNAcase

From Wikipedia, the free encyclopedia
OGA crystal structure dimer.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesOGA, MEA5, NCOAT, meningioma expressed antigen 5 (hyaluronidase), MGEA5, O-GlcNAcase
External IDsOMIM: 604039 MGI: 1932139 HomoloGene: 8154 GeneCards: OGA
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 10: 101.78 – 101.82 MbChr 19: 45.74 – 45.77 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Protein O-GlcNAcase (EC, OGA, glycoside hydrolase O-GlcNAcase, O-GlcNAcase, BtGH84, O-GlcNAc hydrolase) is an enzyme with systematic name (protein)-3-O-(N-acetyl-D-glucosaminyl)-L-serine/threonine N-acetylglucosaminyl hydrolase.[5][6][7][8][9] OGA is encoded by the OGA gene. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction:

  1. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-serine + H2O ⇌ [protein]-L-serine + N-acetyl-D-glucosamine
  2. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-threonine + H2O ⇌ [protein]-L-threonine + N-acetyl-D-glucosamine


Protein O-GlcNAcase
Cartoon Image of OGA.jpg
EC no.
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum

Other names include:

  • Nuclear cytoplasmic O-GlcNAcase and acetyltransferase


The human OGA gene is capable of producing two different transcripts, each capable of encoding a different OGA isoform. The long isoform L-OGA, a bifunctional enzyme that possess a glycoside hydrolase activity and a pseudo histone-acetyl transferase domain, primarily resides in the cytoplasm and the nucleus. The short isoform S-OGA, which only exhibit the glycoside hydrolase domain, was initially described as residing within the nucleus. However, more recent work showed that S-OGA is located in mitochondria and regulates reactive oxygen production in this organelle.[10] Another isoform, resulting from proteolytic cleavage of L-OGA, has also been described. All three isoforms exhibit glycoside hydrolase activity.[11]


Protein O-GlcNAcases belong to glycoside hydrolase family 84 of the carbohydrate active enzyme classification.[12] Homologs exist in other species as O-GlcNAcase is conserved in higher eukaryotic species. In a pairwise alignment, humans share 55% homology with Drosophila and 43% with C. elegans. Drosophila and C. elegans share 43% homology. Among mammals, the OGA sequence is even more highly conserved. The mouse and the human have 97.8% homology. However, OGA does not share significant homology with other proteins. However, short stretches of about 200 amino acids in OGA have homology with some proteins such as hyaluronidase, a putative acetyltransferase, eukaryotic translation elongation factor-1γ, and the 11-1 polypeptide.[13]


Protein O-GlcNAcylation[edit]

Metabolic pathway for OGA

O-GlcNAcylation is a form of glycosylation, the site-specific enzymatic addition of saccharides to proteins and lipids. This form of glycosylation is with O-linked β-N-acetylglucosamine or β-O-linked 2-acetamido-2-deoxy-D-glycopyranose (O-GlcNAc). In this form, a single sugar (β-N-acetylglucosamine) is added to serine and threonine residues of nuclear or cytoplasmic proteins. Two conserved enzymes control this glycosylation of serine and threonine: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). While OGT catalyzes the addition of O-GlcNAc to serine and threonine, OGA catalyzes the hydrolytic cleavage of O-GlcNAc from post-transitionally modified proteins.[14]

OGA is a member of the family of hexosaminidases. However, unlike lysosomal hexosaminidases, OGA activity is the highest at neutral pH (approximately 7) and it localizes mainly to the cytosol. OGA and OGT are synthesized from two conserved genes and are expressed throughout the human body with high levels in the brain and pancreas. The products of O-GlcNAc and the process itself plays a role in embryonic development, brain activity, hormone production, and a myriad of other activities.[15][16]

Over 600 proteins are targets for O-GlcNAcylation. While the functional effects of O-GlcNAc modification is not fully known, it is known that O-GlcNAc modification impacts many cellular activities such as lipid/carbohydrate metabolism and hexosamine biosynthesis. Modified proteins may modulate various downstream signaling pathways by influencing transcription and proteomic activities.[17]

Mechanism and inhibition[edit]

a. Inhibitors for OGA b. Cross section of active site

OGA catalyzes O-GlcNAc hydrolysis via an oxazoline reaction intermediate.[18] Stable compounds which mimic the reaction intermediate can act as selective enzyme inhibitors. Thiazoline derivatives of GlcNAc can be used as a reaction intermediate. An example of this includes Thiamet-G as shown on the right. A second form of inhibition can occur from the mimicry of the transition state. The GlcNAcstatin family of inhibitors exploit this mechanism in order to inhibit OGA activity. For both types of inhibitors, OGA can be selected apart from the generic lysosomal hexosaminidases by elongating the C2 substituent in their chemical structure. This takes advantage of a deep pocket in OGA's active site that allow it to bind analogs of GlcNAc.[19]

There is potential for regulation of O-GlcNAcase for the treatment of Alzheimer's disease. When the tau protein in the brain is hyperphosphorylated, neurofibrillary tangles form, which are a pathological hallmark for neurodegenerative diseases such as Alzheimer's disease. In order to treat this condition, OGA is targeted by inhibitors such as Thiamet-G in order to prevent O-GlcNAc from being removed from tau, which assists in preventing tau from becoming phosphorylated.[20]


X-ray structures are available for a range of O-GlcNAcase proteins. The X-ray structure of human O-GlcNAcase in complex with Thiamet-G identified the structural basis of enzyme inhibition.[21]

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198408 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025220 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Wells L, Gao Y, Mahoney JA, Vosseller K, Chen C, Rosen A, Hart GW (January 2002). "Dynamic O-glycosylation of nuclear and cytosolic proteins: further characterization of the nucleocytoplasmic beta-N-acetylglucosaminidase, O-GlcNAcase". The Journal of Biological Chemistry. 277 (3): 1755–61. doi:10.1074/jbc.M109656200. PMID 11788610.
  6. ^ Cetinbaş N, Macauley MS, Stubbs KA, Drapala R, Vocadlo DJ (March 2006). "Identification of Asp174 and Asp175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants". Biochemistry. 45 (11): 3835–44. doi:10.1021/bi052370b. PMID 16533067.
  7. ^ Dennis RJ, Taylor EJ, Macauley MS, Stubbs KA, Turkenburg JP, Hart SJ, et al. (April 2006). "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology. 13 (4): 365–71. doi:10.1038/nsmb1079. PMID 16565725. S2CID 9239755.
  8. ^ Kim EJ, Kang DO, Love DC, Hanover JA (June 2006). "Enzymatic characterization of O-GlcNAcase isoforms using a fluorogenic GlcNAc substrate". Carbohydrate Research. 341 (8): 971–82. doi:10.1016/j.carres.2006.03.004. PMID 16584714.
  9. ^ Dong DL, Hart GW (July 1994). "Purification and characterization of an O-GlcNAc selective N-acetyl-beta-D-glucosaminidase from rat spleen cytosol". The Journal of Biological Chemistry. 269 (30): 19321–30. doi:10.1016/S0021-9258(17)32170-1. PMID 8034696.
  10. ^ Pagesy P, Bouaboud A, Feng Z, Hulin P, Issad T (June 2022). "Short O-GlcNAcase is targeted to the mitochondria and regulates mitochondrial reactive oxygen species level". Cells. 11 (11): 1827. doi:10.3390/cells11111827. PMC 9180253. PMID 35681522. S2CID 9180253.
  11. ^ Li J, Huang CL, Zhang LW, Lin L, Li ZH, Zhang FW, Wang P (July 2010). "Isoforms of human O-GlcNAcase show distinct catalytic efficiencies". Biochemistry. Biokhimiia. 75 (7): 938–43. doi:10.1134/S0006297910070175. PMID 20673219. S2CID 2414800.
  12. ^ Greig, Ian; Vocadlo, David. "Glycoside Hydrolase Family 84". Cazypedia. Retrieved 28 March 2017.
  13. ^ Gao Y, Wells L, Comer FI, Parker GJ, Hart GW (March 2001). "Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain". The Journal of Biological Chemistry. 276 (13): 9838–45. doi:10.1074/jbc.M010420200. PMID 11148210.
  14. ^ Lima VV, Rigsby CS, Hardy DM, Webb RC, Tostes RC (2009). "O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension". Journal of the American Society of Hypertension. 3 (6): 374–87. doi:10.1016/j.jash.2009.09.004. PMC 3022480. PMID 20409980.
  15. ^ Förster S, Welleford AS, Triplett JC, Sultana R, Schmitz B, Butterfield DA (September 2014). "Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (9): 1333–9. doi:10.1016/j.bbadis.2014.05.014. PMC 4140188. PMID 24859566.
  16. ^ Shafi R, Iyer SP, Ellies LG, O'Donnell N, Marek KW, Chui D, et al. (May 2000). "The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5735–9. Bibcode:2000PNAS...97.5735S. doi:10.1073/pnas.100471497. PMC 18502. PMID 10801981.
  17. ^ Love DC, Ghosh S, Mondoux MA, Fukushige T, Wang P, Wilson MA, et al. (April 2010). "Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity". Proceedings of the National Academy of Sciences of the United States of America. 107 (16): 7413–8. Bibcode:2010PNAS..107.7413L. doi:10.1073/pnas.0911857107. PMC 2867743. PMID 20368426.
  18. ^ Dennis RJ, Taylor EJ, Macauley MS, Stubbs KA, Turkenburg JP, Hart SJ, et al. (April 2006). "Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity". Nature Structural & Molecular Biology. 13 (4): 365–71. doi:10.1038/nsmb1079. PMID 16565725. S2CID 9239755.
  19. ^ Alonso J, Schimpl M, van Aalten DM (December 2014). "O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling?". The Journal of Biological Chemistry. 289 (50): 34433–9. doi:10.1074/jbc.R114.609198. PMC 4263850. PMID 25336650.
  20. ^ Lim S, Haque MM, Nam G, Ryoo N, Rhim H, Kim YK (August 2015). "Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors". International Journal of Molecular Sciences. 16 (9): 20212–24. doi:10.3390/ijms160920212. PMC 4613198. PMID 26343633.
  21. ^ Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, et al. (June 2017). "Structural and functional insight into human O-GlcNAcase". Nature Chemical Biology. 13 (6): 610–612. doi:10.1038/nchembio.2358. PMC 5438047. PMID 28346405.

Further reading[edit]

External links[edit]